The investigational chemotherapeutic drug flavone acetic acid (FAA) acts as an immunomodulator by augmenting natural killer activity in both humans and rodents after in vivo administration. The accumulated data derived from a series of experiments also demonstrates that FAA synergizes with interleukin 2 (IL-2) for the treatment of murine renal cancer. The immunomodulatory and immunotherapeutic effects of FAA are strictly dose dependent with doses of FAA > 150 mg/kg effectively synergizing with IL-2, and doses < 150 mg/kg exhibiting very little therapeutic effect. The antitumor and immunomodulatory effects of FAA are more pronounced in vivo than in vitro. Collectively, these results suggested that cytokines induced by FAA may contribute to these effects, and that the induction of such cytokines may also be very dose dependent. Studies were therefore initiated to investigate whether the in vivo administration of FAA would alter the expression of cytokine mRNA in leukocytes. Splenic leukocytes or liver nonparenchymal cells from untreated and FAA-treated mice were used as a source of RNA for Northern blot analysis. Interferon α and interferon γ mRNA in the spleen was upregulated within 1.5 h after FAA administration, with peak induction occurring by about 2 h. An upregulation of tumor necrosis factor α mRNA was detected in the spleen by 0.5–1 h after treatment with peak induction occurring by 1–1.5 h. Induction of tumor necrosis factor α mRNA was also detected in hepatic nonparenchymal cells. No up-regulation of splenic mRNA for tumor necrosis factor β, IL-1α or β, or IL-2 was detected after FAA administration. IFN and TNF activities were detectable in the serum by bioassay immediately following the appearance of mRNA in FAA mice. The observed up-regulation by FAA of cytokine mRNA and the corresponding serum protein was strictly dose dependent with substantial induction of both mRNA and proteins occurring only at FAA doses ≥ 150 mg/kg, a dose range also shown to be the minimum required for immunomodulatory and immunotherapeutic effects. In summary, these results demonstrate that FAA acts as a potent inducer of at least three cytokines in vivo, and suggest that the immunomodulatory and immunotherapeutic effects of FAA may be partially mediated by these induced cytokines.

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This project was funded in part with Federal funds from the Department of Health and Human Services, under Contract NO1-CO-74102 with Program Resources, Inc.

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